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Clinical and Translational Medicine
Published in: Clinical and Translational Medicine 1/2017

Open Access 01-12-2017 | Review

Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants

Author: Murray M. Bern

Published in: Clinical and Translational Medicine | Issue 1/2017

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Abstract

Extracellular vesicles (EV) are blebs of cellular membranes, which entrap small portions of subjacent cytosol. They are released from a variety of cells, circulate in the blood for an unknown length of time and come to rest on endothelial surfaces. They contribute to an array of physiologic pathways, the complexity of which is still being investigated. They contribute to metastatic malignant cell implants and tumor-related angiogenesis, possibly abetted by the tissue factor that they carry. It is thought that the adherence of the EV to endothelium is dependent upon a combination of their P-selectin glycoprotein ligand-1 and exposed phosphatidylserine, the latter of which is normally hidden on the inner bilayer of the intact cellular membrane. This manuscript reviews what is known about EV origins, their clearance from the circulation and how they contribute to malignant cell implants upon endothelium surfaces and subsequent tumor growth.
Literature
1.
Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913. doi:10.​3402/​jev.​v3.​26913 PubMedCrossRef
2.
3.
Kreimer S, Belov AM, Ghiran I, Murthy SK, Frank DA, Ivanov AR (2015) Mass-spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics. J Proteome Res 14:2367–2384. doi:10.​1021/​pr501279t PubMedCrossRef
4.
5.
van der Pol E, Böing AN, Gool EL, Nieuwland R (2016) Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J Thromb Haemost 14:48–56. doi:10.​1111/​jth.​13190 PubMedCrossRef
6.
7.
8.
9.
Hussein MA, Böing AN, Biró E, Hoek FJ, Vogel GM, Meuleman DG et al (2008) Phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties. Thromb Res 121:865–871CrossRef
10.
11.
Collier ME, Mah PM, Xiao Y, Maraveyas A, Ettelair C (2013) Microparticle-associated tissue factor is recycled by endothelial cells resulting in enhanced surface tissue factor activity. Thromb Haemost 110:966–976. doi:10.​1160/​TH13-01-0055 PubMedCrossRef
12.
Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E et al (2003) Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 197:1585–1598PubMedPubMedCentralCrossRef
13.
Hrachovinová I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A et al (2003) Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9:1020–1025PubMedCrossRef
14.
15.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNA is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. doi:10.​1038/​ncb1596 PubMedCrossRef
16.
17.
18.
19.
20.
21.
22.
23.
Johnstone RM, Mathew A, Mason AB, Teng K (1991) Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J Cell Physiol 147:27–36PubMedCrossRef
24.
Stace CL, Ktistakis NT (2006) Phosphatidic acid- and phosphatidylserine-binding proteins. Biochem Biophys Acta 1761:913–926PubMed
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Nakai W, Yoshida T, Diez D, Miyatake Y, Nishibu T, Imawaka N et al (2016) A novel affinity-based method for the isolation of highly purified extracellular vesicles. Sci Rep 6(33935):1–11. doi:10.​1038/​srep33935
35.
Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S et al (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439PubMedCrossRef
36.
37.
38.
Charrin S, Manie S, Oualid M, Billard M, Boucheix C, Rubinstein E (2002) Differential stability of tetraspanin–tetraspanin interactions: role of palmitoylation. FEBS Lett 516:139–144PubMedCrossRef
39.
40.
41.
Jansen F, Yang X, Hoyer FF, Paul K, Heiermann N, Becher MU et al (2012) Endothelial microparticle uptake in target cells in annexin 1/phosphatidylserine receptor dependent and prevents apoptosis. Arterioscler Thromb Vasc Biol 32:1925–1935. doi:10.​1161/​ATVBAHA.​112.​253229 PubMedCrossRef
42.
Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J (2002) Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418:200–203PubMedCrossRef
43.
44.
Willekens F, Werre JM, Kruijt JK, Roerdinkholder-Stoelwinder B, Groenen-Döpp YA, van den Bos AG et al (2005) Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105:2141–2145PubMedCrossRef
45.
Al Faraj A, Gazeau F, Wilhelm C, Devue C, Guérin CL, Péchoux C et al (2012) Endothelial cell-derived microparticles loaded with iron oxide nanoparticles: feasibility of MR imaging monitoring in mice. Radiology 263:169–178. doi:10.​1148/​radiol.​11111329 PubMedCrossRef
46.
47.
48.
Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760PubMedCrossRef
49.
50.
Chou J, Mackman N, Merrill-Skoloff G, Pederson B, Furie BC, Furie B (2004) Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 104:3190–3197PubMedCrossRef
51.
Simoncini S, Njock MS, Robert S, Camoin-Jau L, Sampol J, Harlé JR et al (2009) TRAIL/Apo2L mediates the release of procoagulant endothelial microparticles induced by thrombin in vitro. A potential mechanism linking inflammation and coagulation. Circ Res 104:943–951. doi:10.​1161/​CIRCRESAHA.​108.​183285 PubMedCrossRef
52.
53.
54.
55.
Cambien B, Wagner DD (2004) A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med 10:179–186PubMedCrossRef
56.
57.
58.
Furie B, Furie BC (2004) Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 10:171–178PubMedCrossRef
59.
Vandendries ER, Furie BC, Furie B (2004) Role of P-selectin and PSGL-I in coagulation and thrombosis. Thromb Haemost 92:459–466PubMed
60.
McEver RP, Beckstead JH, Moore KL, Marshall-Carlson L, Bainton DF (1989) GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel–Palade bodies. J Clin Investig 84:92–99PubMedPubMedCentralCrossRef
61.
Montoro-Garcia S, Shantsila E, Hermández-Romero D, Jover E, Valdés M, Marin F et al (2014) Small-size platelet microparticles trigger platelet and monocyte functionality and modulate thrombogenesis via P-selectin. Br J Haematol 166:571–580. doi:10.​1111/​bjh.​12913 PubMedCrossRef
62.
Setty BN, Betal SG (2008) Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes. Blood 111:905–914PubMedPubMedCentralCrossRef
63.
Lopez-Vilchez I, Diaz-Ricart M, Galan AM, Roque M, Caballo C, Molina P et al (2016) Internalization of tissue factor-rich microvesicles by platelets occurs independently of GPIIb-IIIa, and involves CD36 receptor, serotonin transporter and cytoskeletal assembly. J Cell Biochem 117:448–457. doi:10.​1002/​jcb.​25293 PubMedCrossRef
64.
Manodori AB, Barabino GA, Lubin BH, Kuypers FA (2000) Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood 95:1293–1300PubMed
65.
Sabatier F, Roux V, Anfosso F, Camoin L, Sampol J, Dignat-George F (2002) Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 99:3962–3970PubMedCrossRef
66.
Furie B, Furie BC, Flaumenhaft R, Zwicker JI (2014) Animal models of arterial and venous thrombosis. Blood 124:SCI 2CrossRef
67.
Reinhardt C, von Brühl ML, Manukyan D, Grahl L, Lorenz M, Altmann B et al (2008) Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Investig 118:1110–1122. doi:10.​1172/​JCI32376 PubMedPubMedCentral
68.
69.
Hamilton KK, Hattori R, Esmon CT, Sims PJ (1990) Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for the assembly of the prothrombinase enzyme complex. J Biol Chem 265:3809–3814PubMed
70.
71.
Mobarrez F, He S, Bröijersen A, Wiklund B, Antovic A, Antovic J et al (2011) Atrovastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease. Thromb Haemost 106:344–352. doi:10.​1160/​TH10-12-0810 PubMedCrossRef
72.
Romano M, Mezzetti A, Marulli C, Ciabattoni G, Febo F, Di Ienno S et al (2000) Fluvastatin reduces soluble P-selectin and ICAM-1 levels on hypercholesterolemic patients: role of nitric oxide. J Investig Med 48:183–189PubMed
73.
Berkan O, Katrancioglu N, Ozker E, Ozerdem G, Bakici Z, Yilmaz MB (2009) Reduced P-selectin in hearts pretreated with fluvastatin: a novel benefit for patients undergoing open heart surgery. Thorac Cardiovasc Surg 57:91–95. doi:10.​1055/​s-2008-1039107 PubMedCrossRef
74.
75.
Connor DE, Exner T, Ma DD, Josepth JE (2010) The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein 1B. Thromb Haemost 103:1044–1052. doi:10.​1160/​TH09-09-0644 PubMedCrossRef
76.
Ravanat C, Archipoff G, Beretz A, Freund G, Cazenave JP, Freyssinet JM (1992) Use of annexin-V to demonstrate the role of phosphatidylserine exposure in the maintenance of haemostatic balance by endothelial cells. Biochem J 282:7–13PubMedPubMedCentralCrossRef
77.
78.
Ravassa S, Bennaghmouch A, Kenis H, Lindhout T, Hackeng T, Narula J et al (2005) Annexin A5 down-regulates surface expression of tissue factor: a novel mechanism of regulating the membrane receptor repertoir. J Biol Chem 280:6028–6035PubMedCrossRef
79.
80.
Nabiullina RM, Mustafin IG, Zuev YF, Faizullin DA, Litvinov RI, Zubairova LD (2015) Effect of blood microparticles on the kinetics of polymerization and enzymatic hydrolysis of fibrin. Dokl Biochem Biophys 462:151–154. doi:10.​1134/​S160767291503003​5 PubMedCrossRef
81.
82.
83.
84.
85.
Pultz BDA, Luz FAC, Faria SS, Souza LPF, Tavares PCB, Goulart VA et al (2017) The multifaceted role of extracellular vesicles in metastasis: priming the soil for seeding. Int J Cancer 140:2397–2407. doi:10.​1002/​ijc.​30595 CrossRef
86.
Lobb RJ, van Amerongen R, Wiegmans A, Ham S, Larsen JE, Möller A (2017) Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance. Int J Cancer 141:614–620. doi:10.​1002/​ijc.​30752 PubMedCrossRef
87.
Dolo V, D’Ascenzo S, Violini S, Pompucci L, Festuccia C, Ginestra A et al (1999) Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer cells in vivo and in vitro. Clin Exp Metastasis 17:131–140PubMedCrossRef
88.
Ginestra A, Monea S, Seghezzi G, Dolo V, Nagase H, Mignatti P et al (1997) Urokinase plasminogen activator and gelatinases are associated with membrane vesicles shed by human HT1080 fibrosarcoma cells. J Biol Chem 272:17216–17222PubMedCrossRef
89.
Angelucci A, D’Ascenzo S, Festuccia C, Gravina GL, Bologa M, Dolo V et al (2000) Vesicle-associated urokinase plasminogen activator promotes invasion in prostate cancer cells lines. Clin Exp Metastasis 18:163–170PubMedCrossRef
90.
Brodsky SV, Malinowski K, Golightly M, Jesty J, Goligorsky MS (2002) Plasminogen activator inhibitor-I promotes formation of endothelial microparticles with procoagulant potential. Circulation 106:2372–2378PubMedCrossRef
91.
Lacroix R, Sabatier F, Mialhe A, Basire A, Pannell R, Borghi H et al (2007) Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. Blood 110:2432–2439PubMedPubMedCentralCrossRef
92.
93.
94.
95.
Sierko E, Wojtukiewicz MZ (2004) Platelets and angiogenesis in malignancy. Semin Thromb Hemost 30:95–108PubMedCrossRef
96.
97.
98.
99.
Chen M, Geng JG (2006) P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp 54:75–84. doi:10.​1007/​s00005-006-0010-6 CrossRef
100.
101.
102.
103.
104.
105.
106.
Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM, Osanto S (2007) Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 5:520–527PubMedCrossRef
107.
Hron G, Kollars M, Weber H, Sagaster V, Quehenberger P, Eichinger S et al (2007) Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 97:119–123PubMed
108.
109.
Brunetta DM, De Santis GC, Silva-Pinto AC, Oliveira de Oliveira LC, Covas DT (2015) Hydroxyurea increases plasma concentrations of microparticles and reduces coagulation activation and fibrinolysis in patients with sickle cell disease. Acta Haematol 133:287–294. doi:10.​1159/​000362148 PubMedCrossRef
110.
111.
Fernandez PM, Rickles FR (2002) Tissue factor and angiogenesis in cancer. Curr Opin Hematol 9:401–406PubMedCrossRef
112.
Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A (1995) Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 92:8205–8209PubMedPubMedCentralCrossRef
113.
114.
Thomas GM, Brill A, Mezouar S, Crescence L, Gallant M, Dubois C et al (2015) Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice. J Thromb Haemost 13:1310–1319. doi:10.​1111/​jth.​13002 PubMedPubMedCentralCrossRef
115.
116.
117.
118.
Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W et al (2010) Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteom 9:1085–1099. doi:10.​1074/​mcp.​M900381-MCP200 CrossRef
119.
120.
121.
Pasqualini R, Ruoslahti E (1996) Organ targeting in vivo using phage display peptide libraries. Nature 380:364–366PubMedCrossRef
122.
Rajotte D, Arap W, Hagedorn M, Koivunen E, Pasqualini R, Ruoslahti E (1998) Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J Clin Investig 102:430–437PubMedPubMedCentralCrossRef
123.
124.
125.
Arap W, Kolonin MG, Trepel M, Lahdenranta J, Cardó-Vila M, Giordano RJ et al (2002) Steps toward mapping the human vasculature by phage display. Nat Med 8:121–127PubMedCrossRef
126.
127.
Vallet B, Wiel E (2001) Endothelial cell dysfunction and coagulation. Crit Care Med 29(Suppl 7):36–41CrossRef
128.
129.
130.
Im JH, Fu W, Wang H, Bhatia SK, Hammer DA, Kowalska MA et al (2004) Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64:8613–8619PubMedCrossRef
131.
Biggerstaff JP, Seth N, Amirkhosravi A, Amaya M, Fogarty S, Meyer TV et al (1999) Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo, and enhances experimental metastasis. Clin Exp Metastasis 17:723–730PubMedCrossRef
132.
Bombeli T, Karsan A, Tait JF, Harlan JM (1997) Apoptotic vascular endothelial cells become procoagulant. Blood 89:2429–2442PubMed
133.
134.
Walker B, Towhid ST, Schmid E, Hoffmann SM, Abed M, Münzer P et al (2014) Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors. Am J Physiol Cell Physiol 306:C291–C297. doi:10.​1152/​ajpcell.​00318.​2013 PubMedCrossRef
135.
van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9PubMedCrossRef
136.
137.
Christianson DR, Ozawa MG, Pasqualini R, Arap W (2007) Techniques to decipher molecular diversity by phage display. Methods Mol Biol 357:385–406PubMed
138.
Azzazy HM, Highsmith WE Jr (2002) Phage display technology: clinical applications and recent innovations. Clin Biochem 35:425–445PubMedCrossRef
139.
140.
141.
142.
Li XB, Schluesener HJ, Xu SQ (2006) Molecular addresses of tumors: selection by in vivo phage display. Arch Immunol Ther Exp 54:177–181CrossRef
143.
144.
145.
146.
Kuypers FA, Larkin SK, Emeis JJ, Allison AC (2007) Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity. Thromb Haemost 97:478–486PubMed
147.
148.
149.
150.
Shen XD, Ke B, Zhai Y, Tsuchihashi SI, Gao F, Duarte S et al (2007) Diannexin, a novel annexin V homodimer, protects rat liver transplants against cold ischemia-reperfusion injury. Am J Transplant 7:2463–2471PubMedCrossRef
151.
Metadata
Title
Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants
Author
Murray M. Bern
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2017
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-017-0165-2

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